Editors' ChoiceInfluenza

H5N1 stems the alveolar tide: MSCs to the rescue!

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Science Translational Medicine  13 Apr 2016:
Vol. 8, Issue 334, pp. 334ec59
DOI: 10.1126/scitranslmed.aaf6938

Outbreaks of avian influenza have increased in recent years and represent a major public health hazard, with higher case fatality rates than seasonal flu. In avian flu, severe pulmonary edema is more commonly seen than in seasonal serotypes. Normally, coordinated cellular mechanisms including alveolar fluid clearance keep the lung’s airspaces dry. However, what causes pulmonary edema in avian flu is unknown.

Searching for mechanism, Chan et al. measured fluid transport in cultured, influenza-infected primary human alveolar epithelial cells. In this culture system, cells grown in an upper chamber on a semipermeable membrane actively transport ions and water contained in culture medium into the lower chamber. Alveolar fluid clearance thus modeled can be quantified by measurement of the increase in concentration over 24 hours of FITC-dextran added to the upper chamber. Cells infected with the avian strains H5N1 and H7N9 had markedly decreased alveolar fluid clearance compared with the seasonal strain H1N1, and H5N1 infection also increased FITC-dextran in the lower chamber, suggesting disruption of cellular barrier function. Coculture with mesenchymal stromal cells (MSCs) restored both alveolar fluid clearance and barrier function in alveolar epithelial cells infected with H5N1. Moreover, H5N1 infection decreased expression of ion channels that contribute to alveolar fluid clearance, including the cystic fibrosis transmembrane regulator (CFTR) and subunits of the Na+-K+ ATPase, and also increased expression of cytokines associated with barrier disruption; these effects of avian flu were reversed with MSC coculture.

Exploring in vivo relevance, the authors administered intravenous MSCs to mice with H5N1 5 days after infection. Interestingly, aged (8 to 12 months) but not young (6 to 8 weeks) mice had increased survival and body weight after treatment with MSCs. Furthermore, in the aged group, lung edema and permeability were attenuated by MSC treatment, which markedly increased expression of CFTR in lung lysates.

These findings introduce a new mechanism of pulmonary edema formation in avian flu. Given the mortality benefit in the murine model, these results also provide a rationale for further testing of MSCs in clinical studies. Future studies should probe the mechanism of interaction between age and the mortality benefit associated with MSCs in avian flu.

M. C. W. Chan et al., Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 113, 3621–3626 (2016). [Full Text]

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